Traumatic brain injury decreases cerebral blood flow (CBF) in humans and other mammals. The magnitude of the decrease in CBF and the affected regions of the brain dependent on the type and severity of the injury. Not only can the decrease in CBF, if sufficiently severe, directly damage tissues, but the decrease may also make the brain more susceptible to secondary injury. The aim of this project is provide an in depth understanding of the mechanism responsible for the decrease in CBF. Once understood, strategies could be developed which restore CBF by interfering with the mechanism. Restoration of CBF to the pre-injury rate may reduce the susceptibility of the brain to secondary injury. In the first specific aim we will determine the site along the vascular tree where resistance increases following controlled cortical impact (CI) injury in the rat. Studies are proposed to calculate segmental vascular resistances in the cerebral circulation in sham-injured and CCI-injured rats. Segmental resistances will be calculated after measuring regional cerebral blood flow and microvascular pressure in pial arteries, arterioles, venules, and veins. To extend and complement the studies of segmental resistance, we will determine if the vascular resistance is increased after brain injury as a result of decreased capillary perfusion. In the second specific aim, we will determine if the increased vascular resistance after CCI injury is a result of increased vascular tone (or a state of hyperconstriction). We will employ both in vivo and in vitro studies of cerebral arteries and arterioles to determine where the increased tone occurs in the vascular tree. Additionally, we will determine if the increased tone after injury is a result of a reduction in nitric oxide production or dysfunction of potassium channels in the vascular smooth muscle. We and others have demonstrated that L-arginine restores CBF following traumatic brain injury. The purpose of the third specific aim is to better understand the mechanism of L-arginine effect in restoring CBF. We will determine if L-arginine restores CBF by decreasing the vascular resistance at the site where it is increased after CCI injury. Finally, we will determine if L-arginine restores tone (or contractile state) of the vascular smooth muscle. The specific aim complements and extends studies in the other two projects of this Program Project proposal. We believe that the specific aims in Project 2 of this grant proposal can be successfully accomplished with the techniques and expertise in our group. We further believe that information obtained will be a major step in understanding the pathophysiology of circulatory control after traumatic brain injury.